Mdm2 regulates p53 mRNA translation through inhibitory interactions with ribosomal protein L26.
Mdm2 regulates the p53 tumor suppressor by promoting its proteasome-mediated degradation. Mdm2 and p53 engage in an autoregulatory feedback loop that maintains low p53 activity in nonstressed cells. We now report that Mdm2 regulates p53 levels also by targeting ribosomal protein L26. L26 binds p53 mRNA and augments its translation. Mdm2 binds L26 and drives its polyubiquitylation and proteasomal degradation. In addition, the binding of Mdm2 to L26 attenuates the association of L26 with p53 mRNA and represses L26-mediated augmentation of p53 protein synthesis. Under nonstressed conditions, both mechanisms help maintain low cellular p53 levels by constitutively tuning down p53 translation. In response to genotoxic stress, the inhibitory effect of Mdm2 on L26 is attenuated, enabling a rapid increase in p53 synthesis. The Mdm2-L26 interaction thus represents an additional important component of the autoregulatory feedback loop that dictates cellular p53 levels and activity.
Ofir-Rosenfeld
Yaara
Y
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Boggs
Kristy
K
Michael
Dan
D
Kastan
Michael B
MB
Oren
Moshe
M
D000818:Animals; D002460:Cell Line; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008957:Models, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D014176:Protein Biosynthesis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D054875:Ubiquitination
D012333:RNA, Messenger; C489216:RPL26 protein, human; D012269:Ribosomal Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex